1. Field of Invention
The field of this invention is the process for the preparation of topical compositions used for the treatment of pain, especially pain caused by nerve injury or sympathetically mediated pain. More specifically, the field of this invention relates to n-methyl d-aspartate (NMDA) receptor antagonists, anticholinergic agents, and sympathetic blocking agents, administered topically in a gel or cream base composition, and effective for the relief of pain due to nerve injury or damage.
Sympathetically mediated pain (SMP) is a type of pain in which overactivity of the sympathetic nervous system plays a crucial role. It includes the syndromes of reflex sympathetic dystrophy, causalgia, neuropathic pain secondary to nerve injury, and pain from neuromas. It encompasses all neurogenic pain that is not central and is related to a nerve injury regardless of the cause.
Sympathetically mediated pain (SMP) is a major worldwide epidemic condition. There are greater that 6 million Americans suffering from SMP today. SMP can be so severe that it has been compared to being ten times the intensity caused by childbirth. It is, overall, the most common cause of pain-induced suicide in the US. It is virtually incurable if treatment is initiated greater than 6 months after the disease has been triggered. However, diagnosis in these six months is unusual because, early in the condition, it is so difficult to make.
The signs and symptoms of sympathetically mediated pain are varied. It occurs most often in the limbs but virtually any part of the body can be affected. It can occur at any age, but is often unrecognizable in the very young and is rarely diagnosed at all in its early stage in the absence of a high degree of suspicion. A special bone scan called the triple phase bone scan is diagnostic in some cases in later stages.
There are a number of different types of pain associated with nerve injury or SMP. These types are usually defined by their subjective effects. The specific types of pains which are included in the field of this invention are defined as follows:                Allodynia: pain due to a stimulus that normally does not cause pain, for example as the light touch from air passing over skin.        Hyperpathia: A painful syndrome characterized by increased reaction to a stimulus, especially a repetitive stimulus, as well an increased threshold.        Hyperesthesia: An increased sensitivity to normal stimulation excluding the special senses.        Hyperalgesia: An increased response to a stimulus that is normally painful.        Dysesthesia: An unpleasant abnormal sensation, whether spontaneous or evoked.        Paresthesia: An abnormal Sensation, whether spontaneous or evoked.        Deafferentation Pain: Pain due to loss of sensory input into the central nervous system, as occurs with avulsion of the brachial plexus or other types of lesions of the peripheral nerves or due to pathology of the central nervous system.        Anesthesia Delorosa: Pain in an area or region that is anesthetic (anesthetic means absence of all sensations).        
A classical patient with SMP exhibits hyperpathia, allodynia, swelling, and an electrical shock type parasthesia pain in the limbs. Many SMP patients also experience the other types of pain defined above. The compositions of this invention result in significant relief of all types of SMP defined above.
The field of this invention is the preparation of compositions utilized in the topical treatment of these types of pain.
2. Description of Prior Art
The prior and present treatment of sympathetically mediated pain (SMP) or pain due to nerve damage is directed towards relief of subjective symptoms. Currently, there are several categories of treatments utilized.
I. Oral Medication                1. Standard analgesic medications, including morphine and other opiates, which are generally almost completely ineffective for this type of pain.        2. Ganglionic blocking agents, such as phenoxybenzamine, are more effective than standard analgesics. However, in doses necessary to achieve even minimal pain relief, they can produce totally disabling side effects, such as a sufficiently sharp fall in the blood pressure to render the patient unable to stand or walk without fainting.        3. Tricyclic antidepressants, such as amitriptylline, are mildly effective in about 20% of cases but cause drowsiness.        4. Anti-convulsants, such as carbamazepine, are partially effective in about half of the cases in the relief of electric shock type lancinating parasthesia pain but offer little or no relief from the major burning type of pain.        5. Adrenergic blocking agents, such as yohimbine and terazosine, are only sporadically and temporarily effective. The low blood pressure caused by these agents make their use limited.        
II. Nerve Blocks: Epidural nerve blocks or sympathetic nerve blocks, are invasive procedures using local anesthetics or nerve sclerosing agents, such as phenol or alcohol. Such nerve blocks temporarily or permanently interrupt nerve conduction to and from the painful area. The methods are invasive and temporary, although the analgesic affects may last as long as four to six weeks. However, these methods require a physician pain specialist to inject the patient and are usually performed in an expensive, often inconvenient, hospital setting. Injections using sclerosing agents are fraught with danger, including the formation of neuromas, which can result in worse pain than was originally present. Nerve sclerosing agents are tried as a last resort but rarely are successful.
III. Surgical Procedures: Many have been devised wherein the SMP patient would be subjected to a severing of the spinal cord or of nerves, and even ablation of parts of the brain. However, in the long term, these methods invariably end up with poor results and worse pain. Other surgical procedures costing upwards of 20 thousand dollars each include permanent implantation of peripheral nerve stimulators, spinal cord stimulators, and deep brain stimulators. Aside from being very expensive, these implants are risky and the results are poor.
IV. Topical Treatments: There are currently a limited number of topical treatments available. These agents offer only minimal and short term, usually less than one hour, of pain relief.                1. Geranium oil (applicant's U.S. Pat. No. 5,260,313): The severe pungent odor of strong geranium oil discourages frequent use of this medication. In addition, the relief is generally limited to 2 hours or less.        2. Topical local anesthetics or salicylates: Pain relief occurs in fewer than 25% of the SMP patients. Even then, only half of the pain is relieved.        3. Capsaicin (Cayenne Pepper Extract): This agent applied topically results in an initial burning sensation that discourages the SMP patient from its further use. It provides substantial pain relief for only a small number of SMP patients and then not until after one week of repetitive use.        
V. Miscellaneous Other Methods: Although these techniques are occasionally successful, pain relief results in SMP is considered minimal. These methods include, but are not limited to, guided imagery techniques, acupuncture, hypnosis, physical therapy, and biofeedback.